ClinVar Miner

Submissions for variant NM_003119.4(SPG7):c.703A>G (p.Ile235Val)

gnomAD frequency: 0.00001  dbSNP: rs191022979
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000195778 SCV000252319 uncertain significance not provided 2018-08-28 criteria provided, single submitter clinical testing p.Ile235Val (ATC>GTC): c.703 A>G in exon 5 of the SPG7 gene (NM_003119.2) A variant of unknown significance has been identified in the SPG7 gene. The I235V variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The 1000 Genomes Project reports I235V was observed in 2/120 (1.7%) alleles from individuals of a Mexican ancestry (Los Angeles USA) background, indicating it may be a rare (benign) variant in this population. The I235V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in MITONUC-MITOP panel(s).
Labcorp Genetics (formerly Invitae), Labcorp RCV001853200 SCV002172504 uncertain significance Hereditary spastic paraplegia 7 2023-11-22 criteria provided, single submitter clinical testing This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 235 of the SPG7 protein (p.Ile235Val). This variant is present in population databases (rs191022979, gnomAD 0.04%). This variant has not been reported in the literature in individuals affected with SPG7-related conditions. ClinVar contains an entry for this variant (Variation ID: 215206). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt SPG7 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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